Genomes and Genes
Gene Symbol: Prf1
Description: perforin 1 (pore forming protein)
Alias: Pfn, Pfp, Prf-1, perforin-1, cytolysin, lymphocyte pore-forming protein, pore forming protein
- Murthy A, Li W, Chaganty B, Kamalakaran S, Guentzel M, Seshu J, et al. Tumor necrosis factor alpha production from CD8+ T cells mediates oviduct pathological sequelae following primary genital Chlamydia muridarum infection. Infect Immun. 2011;79:2928-35 pubmed publisher..These results provide compelling new evidence supporting the contribution of CD8(+) T cells and TNF-? production to Chlamydia-induced reproductive tract sequelae...
- Pardo J, Wallich R, Ebnet K, Iden S, Zentgraf H, Martin P, et al. Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin. Cell Death Differ. 2007;14:1768-79 pubmed..The data suggest that activated mast cells contribute, via secreted gzmB, to cell death, increased vascular permeability, leukocyte extravasation and subsequent inflammatory processes in affected tissues. ..
- Baker M, Altman N, Podack E, Levy R. The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J Exp Med. 1996;183:2645-56 pubmed..In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage. ..
- Alsharifi M, Lobigs M, Simon M, Kersten A, Muller K, Koskinen A, et al. NK cell-mediated immunopathology during an acute viral infection of the CNS. Eur J Immunol. 2006;36:887-96 pubmed..This is the first study illustrating an NK cell-mediated immunopathological outcome to an acute viral infection. ..
- Badovinac V, Hamilton S, Harty J. Viral infection results in massive CD8+ T cell expansion and mortality in vaccinated perforin-deficient mice. Immunity. 2003;18:463-74 pubmed..Thus, perforin was essential for resistance to secondary LCMV infection, and, in the absence of perforin, vaccination resulted in lethal disease mediated by dysregulated CD8(+) T cell expansion and cytokine production. ..
- Deb C, Lafrance Corey R, Schmalstieg W, Sauer B, Wang H, German C, et al. CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis. PLoS ONE. 2010;5:e12478 pubmed publisher..Our findings suggest that CD8+ T cells may directly injure demyelinated axons and are therefore a viable therapeutic target to protect axons and motor function in patients with multiple sclerosis. ..
- Smyth M, Thia K, Street S, Cretney E, Trapani J, Taniguchi M, et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med. 2000;191:661-8 pubmed..This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide. ..
- Howe C, Adelson J, Rodriguez M. Absence of perforin expression confers axonal protection despite demyelination. Neurobiol Dis. 2007;25:354-9 pubmed..We conclude that perforin-dependent effector cells such as cytotoxic T cells, gammadelta T cells, and natural killer cells may play a role in axon damage that is dependent upon but separable from demyelination. ..
- Stewart S, Kondos S, Matthews A, D Angelo M, Dunstone M, Whisstock J, et al. The perforin pore facilitates the delivery of cationic cargos. J Biol Chem. 2014;289:9172-81 pubmed publisher..We propose that this facilitated diffusion is due to conserved features of oligomerized MACPF proteins, which may include an anionic lumen. ..
- Jordan M, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104:735-43 pubmed..These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder. ..
- Lu L, Kim H, Werneck M, Cantor H. Regulation of CD8+ regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc Natl Acad Sci U S A. 2008;105:19420-5 pubmed publisher..Further analysis revealed that genetic disruption of the Qa-1-CD94/NKG2A interaction unleashes robust CD8 Treg cell activity that completely abolishes development of EAE. ..
- Kehren J, Desvignes C, Krasteva M, Ducluzeau M, Assossou O, Horand F, et al. Cytotoxicity is mandatory for CD8(+) T cell-mediated contact hypersensitivity. J Exp Med. 1999;189:779-86 pubmed..Thus, cytotoxic CD8(+) T cells, commonly implicated in the host defence against tumors and viral infections, could also mediate harmful delayed-type hypersensitivity reactions. ..
- Murray P, McGavern D, Lin X, Njenga M, Leibowitz J, Pease L, et al. Perforin-dependent neurologic injury in a viral model of multiple sclerosis. J Neurosci. 1998;18:7306-14 pubmed..These studies implicate perforin release by CD8(+) T cells as a potential mechanism by which neurologic deficits are induced after demyelination. ..
- Joeckel L, Wallich R, Martin P, Sánchez Martínez D, Weber F, Martin S, et al. Mouse granzyme K has pro-inflammatory potential. Cell Death Differ. 2011;18:1112-9 pubmed publisher..Together with the finding that IL-1Ra (Anakinra) treatment inhibits virus elimination but not generation of cytotoxic Tc cells in wt mice, the data suggest that Tc cells control LCMV through non-cytotoxic processes that involve gzmK. ..
- Lu L, Ikizawa K, Hu D, Werneck M, Wucherpfennig K, Cantor H. Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity. 2007;26:593-604 pubmed
- Lykens J, Terrell C, Zoller E, Risma K, Jordan M. Perforin is a critical physiologic regulator of T-cell activation. Blood. 2011;118:618-26 pubmed publisher..We conclude that perforin-dependent cytotoxicity has an immunoregulatory role that is distinguishable from its pathogen clearance function and limits T-cell activation in the physiologic context by suppressing antigen presentation. ..
- Balkow S, Kersten A, Tran T, Stehle T, Grosse P, Museteanu C, et al. Concerted action of the FasL/Fas and perforin/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection. J Virol. 2001;75:8781-91 pubmed
- Deb C, Lafrance Corey R, Zoecklein L, Papke L, Rodriguez M, Howe C. Demyelinated axons and motor function are protected by genetic deletion of perforin in a mouse model of multiple sclerosis. J Neuropathol Exp Neurol. 2009;68:1037-48 pubmed publisher..These results suggest that perforin is a key mediator of axon injury and lend additional support to the hypothesis that CD8 T cells are primarily responsible for axon damage in multiple sclerosis. ..
- Takeda K, Cretney E, Hayakawa Y, Ota T, Akiba H, Ogasawara K, et al. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood. 2005;105:2082-9 pubmed..This study is the first to describe the concomitant maturation of NK cell effector function with surface phenotype in vivo and implies an important defense role for NK cell TRAIL in the developing immune system. ..
- Street S, Cretney E, Smyth M. Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis. Blood. 2001;97:192-7 pubmedPerforin (pfp) and interferon-gamma (IFN-gamma) together in C57BL/6 (B6) and BALB/c mouse strains provided optimal protection in 3 separate tumor models controlled by innate immunity...
- Badovinac V, Tvinnereim A, Harty J. Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-gamma. Science. 2000;290:1354-8 pubmed..Thus, perforin and IFN-gamma regulate distinct elements of CD8+ T cell homeostasis independently of their role as antimicrobial effector molecules. ..
- Smyth M, Thia K, Cretney E, Kelly J, Snook M, Forbes C, et al. Perforin is a major contributor to NK cell control of tumor metastasis. J Immunol. 1999;162:6658-62 pubmed..Depletion of NK subsets resulted in greater numbers of metastases than observed in perforin-deficient mice, suggesting that perforin-independent effector functions of NK cells may also contribute to protection from tumor metastasis. ..
- Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen K, et al. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994;369:31-7 pubmed..The mice fail to clear lymphocytic choriomeningitis virus and they eliminate fibrosarcoma tumour cells with reduced efficiency. Perforin is therefore a key effector molecule for T-cell- and natural killer-cell-mediated cytolysis. ..
- Cretney E, Takeda K, Yagita H, Glaccum M, Peschon J, Smyth M. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol. 2002;168:1356-61 pubmed..TRAIL gene-targeted mice were also more sensitive to the chemical carcinogen methylcholanthrene. These results substantiated TRAIL as an important natural effector molecule used in the host defense against transformed cells. ..
- Terrell C, Jordan M. Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. Blood. 2013;121:5184-91 pubmed publisher..Thus, selective cytotoxic "pruning" of DC populations by CD8(+) T cells limits T-cell activation and protects against the development of HLH and potentially other immunopathological conditions. ..
- Silverio J, Pereira I, Cipitelli M, Vinagre N, Rodrigues M, Gazzinelli R, et al. CD8+ T-cells expressing interferon gamma or perforin play antagonistic roles in heart injury in experimental Trypanosoma cruzi-elicited cardiomyopathy. PLoS Pathog. 2012;8:e1002645 pubmed publisher..In T. cruzi infection, most of the CD8(+) T-cells segregated into IFN?(+) perforin (Pfn)(neg) or IFN?(neg)Pfn(+) cell populations. Colonization of the cardiac tissue by anti-T...
- Lowin B, Beermann F, Schmidt A, Tschopp J. A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 1994;91:11571-5 pubmed..We conclude that perforin is a crucial effector molecule in T cell- and NK cell-mediated cytolysis. However, alternative perforin-independent lytic mechanisms also exist. ..
- van den Broek M, Kagi D, Ossendorp F, Toes R, Vamvakas S, Lutz W, et al. Decreased tumor surveillance in perforin-deficient mice. J Exp Med. 1996;184:1781-90 pubmed
- Spielman J, Lee R, Podack E. Perforin/Fas-ligand double deficiency is associated with macrophage expansion and severe pancreatitis. J Immunol. 1998;161:7063-70 pubmed..These studies demonstrate a novel role for perforin in homeostatic regulation of the immune response. ..
- Tay C, Welsh R. Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells. J Virol. 1997;71:267-75 pubmed..These results may explain why the Cmv-lr locus, which maps closely to genes regulating NK cell cytotoxic function, confers an NK cell-dependent resistance to MCMV infection in the spleen but not in the liver. ..
- Loh J, Chu D, O Guin A, Yokoyama W, Virgin H. Natural killer cells utilize both perforin and gamma interferon to regulate murine cytomegalovirus infection in the spleen and liver. J Virol. 2005;79:661-7 pubmed..of the acute phase of murine cytomegalovirus (MCMV) infection and have been reported to utilize perforin (Pfp)- and gamma interferon (IFN-gamma)-dependent effector mechanisms in an organ-specific manner to regulate MCMV ..
- Shresta S, Graubert T, Thomas D, Raptis S, Ley T. Granzyme A initiates an alternative pathway for granule-mediated apoptosis. Immunity. 1999;10:595-605 pubmed..The gzmA pathway appears to function independently from gzmB and may therefore provide a critical "back-up" system when gzmB is inhibited in the target cell. ..
- Simon M, Hausmann M, Tran T, Ebnet K, Tschopp J, ThaHla R, et al. In vitro- and ex vivo-derived cytolytic leukocytes from granzyme A x B double knockout mice are defective in granule-mediated apoptosis but not lysis of target cells. J Exp Med. 1997;186:1781-6 pubmed..This suggests that gzmA and B are critical for Tc/NK granule- mediated nucleolysis, with gzmB being the main contributor, while target cell lysis is due solely to perforin and independent of both proteases. ..
- Noval Rivas M, Hazzan M, Weatherly K, Gaudray F, Salmon I, Braun M. NK cell regulation of CD4 T cell-mediated graft-versus-host disease. J Immunol. 2010;184:6790-8 pubmed publisher..These results highlight the potential role played by NK cells in controlling the Ag-specific CD4+ T cells responsible for chronic GVHD. ..
- Fehniger T, Cai S, Cao X, Bredemeyer A, Presti R, French A, et al. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity. 2007;26:798-811 pubmed..These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation. ..
- McGavern D, Christen U, Oldstone M. Molecular anatomy of antigen-specific CD8(+) T cell engagement and synapse formation in vivo. Nat Immunol. 2002;3:918-25 pubmed..In addition, we have established an in vivo approach for assessing the intricacies of antigen-specific T cell activation, migration, engagement, memory and other defining elements of adaptive immunity. ..
- Hu D, Ikizawa K, Lu L, Sanchirico M, Shinohara M, Cantor H. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol. 2004;5:516-23 pubmed..These findings delineate a Qa-1-dependent T cell-T cell inhibitory interaction that prevents the pathogenic expansion of autoreactive CD4 T cell populations and consequent autoimmune disease. ..
- Walsh C, Matloubian M, Liu C, Ueda R, Kurahara C, Christensen J, et al. Immune function in mice lacking the perforin gene. Proc Natl Acad Sci U S A. 1994;91:10854-8 pubmed..We conclude that perforin-less -/- mice retain and express the Fas lytic pathway as expressed in vitro but that this pathway is insufficient to clear an LCMV infection in vivo. ..
- Susanto O, Stewart S, Voskoboinik I, Brasacchio D, Hagn M, Ellis S, et al. Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis. Cell Death Differ. 2013;20:1183-93 pubmed publisherHuman and mouse granzyme (Gzm)B both induce target cell apoptosis in concert with pore-forming perforin (Pfp); however the mechanisms by which other Gzms induce non-apoptotic death remain controversial and poorly characterised...
- Smyth M, Street S, Trapani J. Cutting edge: granzymes A and B are not essential for perforin-mediated tumor rejection. J Immunol. 2003;171:515-8 pubmed
- Waggoner S, Taniguchi R, Mathew P, Kumar V, Welsh R. Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J Clin Invest. 2010;120:1925-38 pubmed publisher..These results illustrate the importance of NK cell self-tolerance to activated CD8+ T cells and demonstrate how an apparent T cell-associated persistent infection can actually be regulated by NK cells. ..
- Gebhard J, Perry C, Harkins S, Lane T, Mena I, Asensio V, et al. Coxsackievirus B3-induced myocarditis: perforin exacerbates disease, but plays no detectable role in virus clearance. Am J Pathol. 1998;153:417-28 pubmed..Thus, the chemokine pathway offers a second route of intervention to diminish myocarditis and its sequelae, while permitting the host to eradicate the virus. ..
- Gregg R, Nichols L, Chen Y, Lu B, Engelhard V. Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice. J Immunol. 2010;184:1909-17 pubmed publisher..Genetic ablation of CXCR3 or IFN-gamma also resulted in scarce CD8 T cell infiltration into the skin. Our results identify unexpected complexity in vitiligo development and point toward possible therapeutic interventions. ..
- Medana I, Li Z, Flügel A, Tschopp J, Wekerle H, Neumann H. Fas ligand (CD95L) protects neurons against perforin-mediated T lymphocyte cytotoxicity. J Immunol. 2001;167:674-81 pubmed..5 h, reflecting perforin-dependent cell lysis. FasL seems to protect neurons by blocking degranulation of CTLs, since CD3-induced release of cytotoxic granules was reduced by coapplication of Fas-specific Abs or rFasL. ..
- Kojima H, Shinohara N, Hanaoka S, Someya Shirota Y, Takagaki Y, Ohno H, et al. Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. Immunity. 1994;1:357-64 pubmed..These data not only confirmed the primary role of perforin but simultaneously revealed a major contribution of a perforin-independent Fas-mediated pathway in antigen-specific cytolysis. ..
- Schiller N, Boisvert W, Curtiss L. Inflammation in atherosclerosis: lesion formation in LDL receptor-deficient mice with perforin and Lyst(beige) mutations. Arterioscler Thromb Vasc Biol. 2002;22:1341-6 pubmed..with NK cell-defective Lyst(beige) mice (creating beige,LDLr-/- mice) and with perforin-deficient mice (creating Pfp-/-,LDLr-/- mice). Male mice (8 to 10 weeks old) were fed a high-fat diet to induce atherosclerosis...
- Trapani J, Kwon B, Kozak C, Chintamaneni C, Young J, Dupont B. Genomic organization of the mouse pore-forming protein (perforin) gene and localization to chromosome 10. Similarities to and differences from C9. J Exp Med. 1990;171:545-57 pubmedGenomic clones encompassing the entire coding region of the mouse lymphocyte pore-forming protein gene (Pfp) have been isolated and used to determine its intron-exon organization...
- Ma H, Whitters M, Konz R, Senices M, Young D, Grusby M, et al. IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma. J Immunol. 2003;171:608-15 pubmed..We conclude that IL-21 immunotherapy warrants clinical evaluation as a potential treatment for cancer. ..
- Law R, Lukoyanova N, Voskoboinik I, Caradoc Davies T, Baran K, Dunstone M, et al. The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature. 2010;468:447-51 pubmed publisher..molecule, comprising an amino-terminal membrane attack complex perforin-like (MACPF)/cholesterol dependent cytolysin (CDC) domain followed by an epidermal growth factor (EGF) domain that, together with the extreme carboxy-..
- Kagi D, Odermatt B, Seiler P, Zinkernagel R, Mak T, Hengartner H. Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med. 1997;186:989-97 pubmed..However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic beta cell loss by less efficient secondary effector mechanisms. ..
- Brown D, Dilzer A, Meents D, Swain S. CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch. J Immunol. 2006;177:2888-98 pubmed..Primed CD4 cells also acquired perforin (Pfn)-mediated cytolytic activity during effector generation, suggesting a second mechanism used by CD4 cells to confer ..
- Kroner A, Ip C, Thalhammer J, Nave K, Martini R. Ectopic T-cell specificity and absence of perforin and granzyme B alleviate neural damage in oligodendrocyte mutant mice. Am J Pathol. 2010;176:549-55 pubmed publisher..These findings have high relevance with regard to our understanding of the pathogenesis of disorders primarily caused by genetically mediated oligodendropathy. ..
- Meuth S, Herrmann A, Simon O, Siffrin V, Melzer N, Bittner S, et al. Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death. J Neurosci. 2009;29:15397-409 pubmed publisher..Thus, electrical silencing is an immediate consequence of MHC I-restricted interaction of CD8(+) T cells with neurons. This mechanism is clearly perforin-dependent and precedes, but is not causally linked, to neuronal cell death. ..
- Silverio J, de Oliveira Pinto L, da Silva A, de Oliveira G, Lannes Vieira J. Perforin-expressing cytotoxic cells contribute to chronic cardiomyopathy in Trypanosoma cruzi infection. Int J Exp Pathol. 2010;91:72-86 pubmed publisher..cruzi strain. This protocol led to acute phase survival in both wild-type and perforin null (pfp(-/-)) mice lineages...
- Mullbacher A, Waring P, Tha Hla R, Tran T, Chin S, Stehle T, et al. Granzymes are the essential downstream effector molecules for the control of primary virus infections by cytolytic leukocytes. Proc Natl Acad Sci U S A. 1999;96:13950-5 pubmed..These results establish that both gzmA and gzmB are indispensable effector molecules acting in concert with perforin in granule exocytosis-mediated host defense against natural viral pathogens...
- Brien J, Uhrlaub J, Nikolich Zugich J. West Nile virus-specific CD4 T cells exhibit direct antiviral cytokine secretion and cytotoxicity and are sufficient for antiviral protection. J Immunol. 2008;181:8568-75 pubmed..These results demonstrate the role of direct effector function of Ag-specific CD4 T cells in preventing severe WNV disease. ..
- Street S, Hayakawa Y, Zhan Y, Lew A, MacGregor D, Jamieson A, et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. J Exp Med. 2004;199:879-84 pubmed..These results reflect a critical role for NK cells and gammadeltaTCR+ T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition. ..
- Riera L, Gariglio M, Valente G, Mullbacher A, Museteanu C, Landolfo S, et al. Murine cytomegalovirus replication in salivary glands is controlled by both perforin and granzymes during acute infection. Eur J Immunol. 2000;30:1350-5 pubmed
- Dudek N, Thomas H, Mariana L, Sutherland R, Allison J, Estella E, et al. Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and Fas pathways. Diabetes. 2006;55:2412-8 pubmed..Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill beta-cells and the surprising blockade of NOD8.3 T-cell-mediated beta-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition. ..
- Lowin B, Hahne M, Mattmann C, Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature. 1994;370:650-2 pubmed..Thus, two complementary, specific cytotoxic mechanisms are functional in CTLs, one based on the secretion of lytic proteins and one which depends on cell-surface ligand-receptor interaction. ..
- Peng S, Moslehi J, Robert M, Craft J. Perforin protects against autoimmunity in lupus-prone mice. J Immunol. 1998;160:652-60 pubmed
- Pardo J, Bosque A, Brehm R, Wallich R, Naval J, Mullbacher A, et al. Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis. J Cell Biol. 2004;167:457-68 pubmed..The ability of gzmA and gzmB to induce multiple independent cell death pathways may be the hosts response to circumvent evasion strategies of pathogens and tumors. ..